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1.
Eur J Pharm Sci ; 167: 105986, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474119

RESUMO

BACKGROUND: Efavirenz is a vital component used to treat HIV-1 infection. Nevertheless, it shows large between-subject variability, which affects both its therapeutic response and adverse effects. OBJECTIVE: To investigate the impact of gene polymorphisms and non-genetic factors on the variability of efavirenz pharmacokinetics and to propose the optimal dose regimens. METHODS: A total of 769 plasma samples from 376 HIV-infected Han Chinese outpatients were collected to develop a population pharmacokinetic model using NONMEM software. The impact of patient demographics, laboratory tests, concomitant medication, and genetic polymorphisms of CYP2B6 and ABCB1 on efavirenz pharmacokinetics were explored. According to the final model, the model-informed dose optimization was conducted. RESULTS: The pharmacokinetics of efavirenz was characterized by a one-compartment model with first-order absorption and elimination. The typical values of the estimated apparent oral clearance, volume of distribution, and absorption rate constant in the final model were 9.44 L/h, 200 L, and 0.727 h - 1, respectively. Efavirenz clearance was significantly influenced by CYP2B6 variants, including rs2099361, rs3745274, and rs2279343, along with albumin and weight. The volume of distribution was affected by albumin and weight. Based on the CYP2B6 polymorphisms of patients, the recommended daily doses of efavirenz were 100 mg for CYP2B6 slow metabolizers, 400 or 600 mg for intermediate metabolizers, and 800 or 1000 mg for extensive metabolizers. CONCLUSIONS: Polymorphisms of CYP2B6, along with albumin and weight, resulted as the predictors of efavirenz pharmacokinetic variability, which could be used in prescribing optimal efavirenz doses.

2.
J Cell Physiol ; 236(9): 6297-6311, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33507567

RESUMO

Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD). Deubiquitinase cylindromatosis (CYLD) has been reported to significantly aggravate vascular smooth muscle cell (VSMC) phenotypic transformation, proliferation, and migration. Here, we aimed to further investigate its roles and underlying mechanisms in the CHD-PAH development. The expression of CYLD in the lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV)-induced PAH rats, pulmonary artery smooth muscle cells (PASMCs) from MCT-AV-induced PAH rats, and human PASMCs (HPASMCs) was evaluated. After infection with CYLD siRNA or pcNDA3.1-CYLD, the proliferation, migration, and apoptosis of HPASMCs were measured using an EdU assay, transwell and scratch wound healing assays, and flow cytometric assay, respectively. An adeno-associated virus (AAV) vector encoding CYLD was used to suppress CYLD expression by being intratracheally instilled in rats 7 days before MCT-AV treatment. The results showed that CYLD was increased in the lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats, and in PASMCs from MCT-AV-induced PAH rats. The contractile-type HPASMCs expressed low levels of CYLD, while the proliferative synthetic-type HPASMCs expressed high levels of CYLD. In addition, CYLD could mediate HPASMC dysfunction, which regulated HPASMC phenotypic transformation and proliferation via the modulation of p38 and ERK activation, while CYLD regulated HPASMC migration via the modulation of p38 activation. In vivo results demonstrated that the local suppression of CYLD expression could attenuate the increased levels of PAH and its associated pulmonary vascular remodeling in MCT-AV-induced PAH rats. Collectively, these results indicated that CYLD might be a potential novel therapeutic target for the prevention of PAH and pulmonary vascular remodeling in CHD-PAH through the modulation of HPASMC dysfunction.

3.
J Mol Cell Cardiol ; 149: 41-53, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32950539

RESUMO

OBJECTIVE: Reportedly, nestin was re-expressed in proliferative synthetic-type pulmonary artery smooth muscle cells (PASMCs) and obligatory for PASMC proliferation in pulmonary arterial hypertension (PAH). Accordingly, nestin is increased in pulmonary vascular lesions of congenital heart disease (CHD)-associated PAH patients. We tested the hypothesis whether nestin was re-expressed in proliferative synthetic-type PASMCs and associated with pulmonary vascular remodeling in CHD-PAH. MATERIALS AND METHODS: Nestin expression was tested using lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV) shunt-induced PAH rats, human PASMCs (HPASMCs), and pulmonary artery endothelial cells (PAECs) and PASMCs from MCT-AV-induced PAH rats. The role and possible mechanism of nestin on HPASMC proliferation, apoptosis, cell cycle and migration were investigated by assays of CCK-8, EdU, TUNEL, flow cytometry, transwell chamber and immunoblotting assays. RESULTS: Nestin was solely expressed in proliferative synthetic-type PASMCs, but rarely detected in PAECs. Nestin was barely detected in normal pulmonary arterioles and occlusive pulmonary vascular lesions. Its expression was robustly increased in developing pulmonary vasculature, but returned to normal levels at the late stage of pulmonary vascular remodeling in lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats. Besides, nestin peaks were consistent with the histological features in lung tissues of MCT-AV-induced PAH rats. Moreover, nestin overexpression effectively promoted HPASMC phenotypic transformation, proliferation, apoptosis resistance and migration via enhancing Wnt/ß-catenin activation. CONCLUSIONS: These data indicated that nestin was re-expressed in proliferative synthetic-type PASMCs and might represent a potential marker of pulmonary vascular remodeling in CHD-PAH.

4.
J Atheroscler Thromb ; 25(5): 454-459, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29212986

RESUMO

AIMS: Platelet endothelial aggregation receptor-1 (PEAR1) is a platelet transmembrane protein that plays an important role on platelet aggregation. The aim of this study was to investigate whether PEAR1 genetic variations are associated with 1-year outcomes in Chinese patients with acute myocardial infarction after percutaneous coronary intervention. METHODS: A total of 647 consecutive Chinese patients with acute myocardial infarction that underwent percutaneous coronary intervention and that were exposed to standard dual antiplatelet therapy with aspirin and clopidogrel were enrolled in this study. Six single nucleotide polymorphisms of PEAR1 were detected using the ligase detection reaction method. The follow-up period was 12 months. RESULTS: Overall, 66 (10.2%) adverse ischemic events occurred. Multivariate Cox regression analysis showed that carriage of the PEAR1 rs56260937 minor allele was an independent predictor of revascularization events (OR=2.15, 95% CI 1.12-4.15, p=0.022) after adjusting for confounding factors. CONCLUSIONS: Genetic testing for PEAR1 variants can be helpful in predicting adverse ischemic events in Chinese patients with acute myocardial infarction after percutaneous coronary intervention.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Marcadores Genéticos , Infarto do Miocárdio/diagnóstico , Intervenção Coronária Percutânea/efeitos adversos , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Doença Aguda , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Prognóstico , Fatores de Tempo
5.
Cell Physiol Biochem ; 41(1): 381-398, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28135716

RESUMO

Backgroud/Aims: The biological function of cardiac troponin I-interacting kinase (TNNI3K), a cardiac-specific functional kinase, is largely unknown. We investigated the effect of human TNNI3K (hTNNI3K) on the differentiation of mouse embryonic stem cells (mESCs) into cardiomyocytes. METHODS: First, the time-space expression of endogenous Tnni3k was detected by real-time polymerase chain reaction (PCR) and western blotting at 16 different time-points over a period of 28 days. Further, action potentials and calcium current with/without 5 µM nifedipine were measured by patch clamp for mESC-derived cardiomyocytes. HTNNI3K and mouse-derived siRNA were transfected into mESC using lentivirus vector to induce hTNNI3K overexpression and knock-down, respectively. RESULTS: The number of troponin-T (cTnT) positive cells was greater in the group with TNNI3K overexpression as compared to that in control group, while less such cells were detected in the mTnni3k knock-down group as evaluated on flow cytometry (FCM) and ImageXpress Micro system. After upregulation of connexin43, cardiac troponin-I (Ctni), Ctni, Gata4 were detected in mESCs with TNNI3K overexpression; however, overexpression of α-Actinin and Mlc2v was not detected. Interestingly, Ctnt, connexin40 and connexin45, the markers of ventricular, atrial, and pacemaker cells, respectively, were detected in by real-time PCR in TNNI3K overexpression group. CONCLUSION: our study indicated that TNNI3K overexpression promoted mESC differentiating into beating cardiomyocytes and induced up-regulating expression of cTnT by PKCε signal pathway, which suggested a modulation of TNNI3K activity as a potential therapeutic approach for ischemic cardiac disease.


Assuntos
MAP Quinase Quinase Quinases/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Cálcio/metabolismo , Diferenciação Celular , Conexina 43/metabolismo , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Células-Tronco Embrionárias Murinas/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/ultraestrutura , Técnicas de Patch-Clamp , Proteína Quinase C-épsilon/metabolismo , Proteínas Serina-Treonina Quinases , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo
6.
Chin Med J (Engl) ; 129(19): 2269-74, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27647183

RESUMO

BACKGROUND: Platelet function tests are widely used in clinical practice to guide personalized antiplatelet therapy. In China, the thromboelastography (TEG) test has been well accepted in clinics, whereas VerifyNow, mainly used for scientific research, has not been used in routine clinical practice. The aim of the current study was to compare these two point-of-care platelet function tests and to analyze the consistency between the two tests for evaluating on-clopidogrel platelet reactivity in Chinese acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI). METHODS: A total of 184 patients admitted to Fuwai Hospital between August 2014 and May 2015 were enrolled in the study. On-clopidogrel platelet reactivity was assessed 3 days after PCI by TEG and VerifyNow using adenosine diphosphate as an agonist. Based on the previous reports, an inhibition of platelet aggregation (IPA) <30% for TEG or a P2Y12 reaction unit (PRU) >230 for VerifyNow was defined as high on-clopidogrel platelet reactivity (HPR). An IPA >70% or a PRU <178 was defined as low on-clopidogrel platelet reactivity (LPR). Correlation and agreement between the two methods were analyzed using the Spearman correlation coefficient (r) and kappa value (κ), respectively. RESULTS: Our results showed that VerifyNow and TEG had a moderate but significant correlation in evaluating platelet reactivity (r = -0.511). A significant although poor agreement (κ = 0.225) in identifying HPR and a significantly moderate agreement in identifying LPR (κ = 0.412) were observed between TEG and VerifyNow. By using TEG as the reference for comparison, the cutoff values of VerifyNow for the Chinese patients in this study were identified as PRU >205 for HPR and PRU <169 for LPR. CONCLUSIONS: By comparing VerifyNow to TEG which has been widely used in clinics, VerifyNow could be an attractive alternative to TEG for monitoring on-clopidogrel platelet reactivity in Chinese patients.


Assuntos
Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea/métodos , Ticlopidina/análogos & derivados , Difosfato de Adenosina/uso terapêutico , Idoso , Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , China , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Sistemas Automatizados de Assistência Junto ao Leito , Receptores Purinérgicos P2Y12/metabolismo , Tromboelastografia , Ticlopidina/uso terapêutico
7.
Thromb Res ; 141: 28-34, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26962983

RESUMO

INTRODUCTION: Platelet Endothelial Aggregation Receptor-1 (PEAR1) is a recently reported platelet transmembrane protein which plays an important role in platelet aggregation. The aim of this study was to investigate whether PEAR1 genetic variations were associated with platelet reactivity as assessed by adenosine diphosphate(ADP)-induced platelet aggregation in Chinese patients treated with aspirin and clopidogrel. METHODS: Patients with coronary heart disease (CHD) who underwent percutaneous coronary intervention (PCI) were enrolled in the study. All patients were on dual antiplatelet therapy with aspirin and clopidogrel. ADP-induced platelet aggregation was measured by thromboelastography and defined as percent inhibition of platelet aggregation (IPA). Patients (n=204) with IPA <30% were identified as high on-treatment platelet reactivity (HPR). Patients (n=201) with IPA >70% were identified as low on-treatment platelet reactivity (LPR). Sixteen single nucleotide polymorphisms (SNPs) of PEAR1 were determined by a method of improved multiple ligase detection reaction. RESULTS: Among the 16 SNPs examined by univariate analysis, 5 SNPs were significantly associated with ADP-induced platelet aggregation. Minor allele C at rs11264580 (p=0.033), minor allele G at rs2644592 (p=0.048), minor allele T at rs3737224 (p=0.033) and minor allele T at rs41273215 (p=0.025) were strongly associated with HPR, whereas homozygous TT genotype at rs57731889 (p=0.009) was associated with LPR. Multivariate logistic regression analysis further revealed that the minor allele T at rs41273215 (p=0.038) was an independent predictor of HPR and the homozygous TT genotype at rs57731889 (p=0.003) was an independent predictor of LPR. CONCLUSIONS: PEAR1 genetic variations were strongly associated with ADP-induced platelet aggregation in Chinese patients with CHD treated with aspirin and clopidogrel. These genetic variations may contribute to the variability in platelet function. The utility of PEAR1 genetic variants in the assessment and prediction of cardiovascular risk warrants further investigation.


Assuntos
Aspirina/uso terapêutico , Doença das Coronárias/terapia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Ticlopidina/análogos & derivados , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Plaquetas/efeitos dos fármacos , China/epidemiologia , Clopidogrel , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Doença das Coronárias/cirurgia , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/métodos , Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/uso terapêutico
8.
Platelets ; 27(1): 75-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25901734

RESUMO

Polymorphisms in platelet receptor genes may influence platelet function. This study aimed to assess the impact of five polymorphisms of genes encoding platelet receptors on the risk of ischemic and bleeding events in ST-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI). 503 consecutive Chinese patients with STEMI after an uneventful PCI and exposed to standard dual antiplatelet therapy for 12 months were enrolled. Polymorphisms of platelet receptors, GPIa (ITGA2, 807C > T, rs1126643), GPVI (GP6, 13254T > C, rs1613662), PAR-1 (F2R, IVS-14A > T, rs168753) and P2Y12 (P2RY12, 34C > T, rs6785930 and H1/H2 haplotype, 52G > T, rs6809699) were detected by the ligase detection reaction. The follow-up period was 12 months. Overall, 34 (6.8%) ischemic events occurred and 46 (9.1%) major bleedings occurred. Multivariate Cox regression analysis showed the carriage of F2R rs168753 minor allele was an independent predictor of the composite ischemic events (HR 0.387, 95% CI 0.193-0.778, p = 0.008) after adjusted for established risk factors. Multivariate logistic regression model identified that carriage of P2RY12 rs6809699 minor allele (OR 2.71, 95% CI 1.298-5.659, p = 0.008) was an independent predictor of major bleedings. The associations were then validated in a second cohort of 483 STEMI patients. In STEMI patients after PCI, F2R rs168753 minor allele could significantly contribute to the risk of ischemic events, and P2RY12 rs6809699 minor allele could predict bleedings. The genetic testing of platelet receptors can be valuable in predicting adverse events in STEMI patients after PCI.


Assuntos
Plaquetas/fisiologia , Integrina alfa2/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/métodos , Receptores Purinérgicos P2Y12/genética , Plaquetas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Ativação Plaquetária , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Resultado do Tratamento
9.
Thromb Res ; 134(5): 970-5, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25217066

RESUMO

INTRODUCTION: This study sought to investigate the relationship of polymorphisms in ABCB1 and the predictive value of thromboelastography (TEG) on bleeding risk in clopidogrel-treated patients with ST-elevation myocardial infarction (STEMI). METHODS: 467 consecutive patients with STEMI undergoing percutaneous coronary intervention (PCI) were enrolled. Twenty tag single nucleotide polymorphisms (SNPs) selected from ABCB1 gene and CYP2C19*2, *3, *17 were detected by the ligase detection reaction. Platelet reactivity was assessed by TEG. The follow-up period was 12months. RESULTS: By receiver operating characteristic curve analysis, the TEG platelet mapping assay value of ADP inhibition had the best predictive value of bleeding academic research consortium definition (BARC) ≥ 3b bleedings, yielding an area under the curve (AUC) of 0.707 (95% CI 0.662-0.749, p=0.009; cut-off value > 93.4%). ADP inhibition can also predict BARC ≥ 3 bleedings with an AUC of 0.594 (95% CI 0.546-0.640, p = 0.05; cut-off value > 92.5%). After adjustment for established risk factors of bleeding including the gain of function CYP2C19*17 allele, age, female gender, renal function, the multivariable logistic regression model demonstrated that ADP inhibition > 92.5% (OR 2.247, 95%CI 1.082-4.665, P=0.03), carriage of rs1045642 (OR 2.943, 95%CI 1.195-7.247, P = 0.019) and rs7779562 (OR 0.453, 95%CI 0.219-0.936, P = 0.032) were independent predictors of BARC ≥ 3 bleedings. These associations were validated in a second cohort of 504 STEMI patients. CONCLUSIONS: In STEMI patients treated with clopidogrel after PCI, the ABCB1 tag SNP rs1045642 is associated with higher risk of bleedings while rs7779562 is associated with lower bleeding risk, and ADP inhibition in TEG has a predictive value of bleedings.


Assuntos
Hemorragia/induzido quimicamente , Hemorragia/genética , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/efeitos adversos , Ticlopidina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Clopidogrel , Feminino , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Intervenção Coronária Percutânea/efeitos adversos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Tromboelastografia , Ticlopidina/efeitos adversos
10.
Heart Lung ; 43(4): 322-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24856224

RESUMO

OBJECTIVE: To investigate plasma levels of CXC-Chemokine Ligand 10 (CXCL10), CXC-Chemokine Ligand 12 (CXCL12) and CXC-Chemokine Ligand 16 (CXCL16) in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS: Plasma levels of biomarkers were measured by enzyme-linked immunosorbent assay in 61 patients with IPAH and 20 healthy volunteers. RESULTS: Plasma CXCL10, CXCL12 and CXCL16 concentrations were increased significantly in IPAH patients compared with controls, and significantly correlated with N-terminal pro-brain natriuretic peptide, tricuspid annulus plane systolic excursion and right ventricular ejection fraction. CONCLUSIONS: Increased levels of CXCL10, CXCL12 and CXCL16 are associated with right ventricular dysfunction in patients with IPAH.


Assuntos
Quimiocinas CXC/sangue , Hipertensão Pulmonar/sangue , Função Ventricular Direita/fisiologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CXCL10/sangue , Quimiocina CXCL12/sangue , Quimiocina CXCL16 , Hipertensão Pulmonar Primária Familiar , Feminino , Hemodinâmica , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Receptores Depuradores/sangue , Volume Sistólico , Disfunção Ventricular Direita/sangue
11.
Respirology ; 19(4): 608-15, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24689969

RESUMO

BACKGROUND AND OBJECTIVE: Pulmonary vascular remodelling and inflammation have been implicated in pulmonary arterial hypertension (PAH). YKL-40, a marker of tissue remodelling and inflammation, has recently been recognized as a risk predictor of cardiovascular and inflammatory diseases. The study aimed to investigate a potential role of YKL-40 in predicting prognosis in idiopathic PAH (IPAH). METHODS: Plasma YKL-40 levels were measured in 82 IPAH patients without current or previous PAH-specific treatment during right heart catheterization and in 54 healthy volunteers. Concurrent data included clinical, haemodynamic and biochemical variables. RESULTS: Plasma YKL-40 levels were increased in IPAH patients compared with control subjects (median, interquartile range: IPAH: 24.90, 17.68-39.78 ng/mL; controls: 16.58, 14.20-19.64 ng/mL; P < 0.001). YKL-40 levels correlated with cardiac index (r = -0.244, P = 0.027) and N-terminal pro-brain natriuretic peptide (NT-proBNP, r = 0.263, P = 0.017). After a median follow-up of 578 days, YKL-40 outperformed NT-proBNP, uric acid, and 6-min walk distance in receiver operating characteristic (ROC) analyses in predicting both clinical worsening (area under the curve (AUC) 0.681) and death (AUC 0.717). Compared with patients with YKL-40 below the ROC-derived cut-off point (24.5 ng/mL), the high YKL-40 group showed higher pulmonary vascular resistance and serum uric acid levels, and showed more clinical worsening events and deaths in Kaplan-Meier analyses. Plasma YKL-40 was independently associated with clinical worsening in univariate and multivariate Cox analyses (all P < 0.05). CONCLUSIONS: Plasma YKL-40 might serve as a promising indicator of disease severity and prognosis in patients with IPAH.


Assuntos
Adipocinas/sangue , Hipertensão Pulmonar Primária Familiar , Inflamação/metabolismo , Lectinas/sangue , Adulto , Biomarcadores/sangue , Cateterismo Cardíaco/métodos , China , Proteína 1 Semelhante à Quitinase-3 , Gerenciamento Clínico , Progressão da Doença , Hipertensão Pulmonar Primária Familiar/sangue , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/mortalidade , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Hipertensão Pulmonar Primária Familiar/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Circulação Pulmonar , Curva ROC , Reprodutibilidade dos Testes
12.
Chin Med J (Engl) ; 126(19): 3728-31, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24112172

RESUMO

BACKGROUND: Iron is a biocorrodible metal that might be used in bioabsorbable stents. This study investigated the effects at the cellular and protein levels of soluble divalent iron (ferrous gluconate) and soluble trivalent iron (ferric chloride) on the proliferation of human aortic smooth muscle cell (HASMC) in vitro. METHODS: The water-soluble tetrazolium (WST-1) test was used to evaluate the effect of iron on proliferation of HASMC and Western blotting was used to measure the levels of signaling proteins involved in proliferative and apoptosis pathways. RESULTS: HASMC proliferation was inhibited in a concentration dependent manner after treatment with soluble divalent and trivalent iron at concentrations of 100-500 µmol/L. Western blotting analysis showed that the proliferating cell nuclear antigen (PCNA) expression following treatment with soluble divalent iron and trivalent iron at 100, 300 and 500 µmol/L was reduced compared to the control. The PCNA expression decreased with increasing iron concentration and to a greater extent with the trivalent iron than with the divalent iron treatment group. The p53 expression was markedly increased in a concentration dependent manner in both iron treatment groups. CONCLUSION: The soluble divalent iron and, to a greater degree trivalent iron, inhibited HASMC proliferation in a dosedependent manner, which may be attributed to reduction of PCNA expression and increase of p53 expression.


Assuntos
Proliferação de Células/efeitos dos fármacos , Ferro/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Miócitos de Músculo Liso/química , Miócitos de Músculo Liso/fisiologia , Antígeno Nuclear de Célula em Proliferação/análise , Proteína Supressora de Tumor p53/análise
13.
Chin Med J (Engl) ; 126(8): 1469-79, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23595379

RESUMO

BACKGROUND: Our previous studies have demonstrated that Tongxinluo (TXL), a traditional Chinese medicine, can protect hearts against no-reflow and reperfusion injury in a protein kinase A (PKA)-dependent manner. The present study was to investigate whether the PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis. METHODS: In a 90-minute ischemia and 3-hour reperfusion model, minipigs were randomly assigned to sham, control, TXL (0.05 g/kg, gavaged one hour prior to ischemia), and TXL + H-89 (a PKA inhibitor, intravenously and continuously infused at 1.0 µg/kg per minute) groups. Myocardial no-reflow, necrosis, edema, and apoptosis were determined by pathological and histological studies. Myocardial activity of PKA and myeloperoxidase was measured by colorimetric method. The expression of PKA, phosphorylated cAMP response element-binding protein (p-CREB) (Ser(133)), tumor necrosis factor α (TNF-α), P-selectin, apoptotic proteins, and aquaporins was detected by Western blotting analysis. RESULTS: TXL decreased the no-reflow area by 37.4% and reduced the infarct size by 27.0% (P < 0.05). TXL pretreatment increased the PKA activity and the expression of Ser(133) p-CREB in the reflow and no-reflow myocardium (P < 0.05). TXL inhibited the ischemia-reperfusion-induced elevation of myeloperoxidase activities and the expression of TNF-α and P-selectin, reduced myocardial edema in the left ventricle and the reflow and no-reflow areas and the expression of aquaporin-4, -8, and -9, and decreased myocytes apoptosis by regulation of apoptotic protein expression in the reflow and no-reflow myocardium. However, addition of the PKA inhibitor H-89 counteracted these beneficial effects of TXL. CONCLUSION: PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis in the reflow and no-reflow myocardium.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Medicamentos de Ervas Chinesas/farmacologia , Edema/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocardite/prevenção & controle , Animais , Aquaporina 4/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Hemodinâmica/efeitos dos fármacos , Suínos , Porco Miniatura
14.
Braz J Med Biol Res ; 46(2): 128-37, 2013 02.
Artigo em Inglês | MEDLINE | ID: mdl-23369981

RESUMO

The phosphorylation of cardiac troponin I (cTnI) plays an important role in the contractile dysfunction associated with heart failure. Human cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific functional kinase that can bind to cTnI in a yeast two-hybrid screen. The purpose of this study was to investigate whether TNNI3K can phosphorylate cTnI at specific sites and to examine whether the phosphorylation of cTnI caused by TNNI3K can regulate cardiac myofilament contractile function. Co-immunoprecipitation was performed to confirm that TNNI3K could interact with cTnI. Kinase assays further indicated that TNNI3K did not phosphorylate cTnI at Ser23/24 and Ser44, but directly phosphorylated Ser43 and Thr143 in vitro. The results obtained for adult rat cardiomyocytes also indicated that enhanced phosphorylation of cTnI at Ser43 and Thr143 correlated with rTNNI3K (rat TNNI3K) overexpression, and phosphorylation was reduced when rTNNI3K was knocked down. To determine the contractile function modulated by TNNI3K-mediated phosphorylation of cTnI, cardiomyocyte contraction was studied in adult rat ventricular myocytes. The contraction of cardiomyocytes increased with rTNNI3K overexpression and decreased with rTNNI3K knockdown. We conclude that TNNI3K may be a novel mediator of cTnI phosphorylation and contribute to the regulation of cardiac myofilament contraction function.


Assuntos
Ventrículos do Coração/citologia , Miócitos Cardíacos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Troponina I/metabolismo , Animais , Imunoprecipitação , Miócitos Cardíacos/química , Miofibrilas , Fosforilação , Plasmídeos , Ratos
15.
Braz. j. med. biol. res ; 46(2): 128-137, 01/fev. 2013. graf
Artigo em Inglês | LILACS | ID: lil-668781

RESUMO

The phosphorylation of cardiac troponin I (cTnI) plays an important role in the contractile dysfunction associated with heart failure. Human cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific functional kinase that can bind to cTnI in a yeast two-hybrid screen. The purpose of this study was to investigate whether TNNI3K can phosphorylate cTnI at specific sites and to examine whether the phosphorylation of cTnI caused by TNNI3K can regulate cardiac myofilament contractile function. Co-immunoprecipitation was performed to confirm that TNNI3K could interact with cTnI. Kinase assays further indicated that TNNI3K did not phosphorylate cTnI at Ser23/24 and Ser44, but directly phosphorylated Ser43 and Thr143 in vitro. The results obtained for adult rat cardiomyocytes also indicated that enhanced phosphorylation of cTnI at Ser43 and Thr143 correlated with rTNNI3K (rat TNNI3K) overexpression, and phosphorylation was reduced when rTNNI3K was knocked down. To determine the contractile function modulated by TNNI3K-mediated phosphorylation of cTnI, cardiomyocyte contraction was studied in adult rat ventricular myocytes. The contraction of cardiomyocytes increased with rTNNI3K overexpression and decreased with rTNNI3K knockdown. We conclude that TNNI3K may be a novel mediator of cTnI phosphorylation and contribute to the regulation of cardiac myofilament contraction function.


Assuntos
Animais , Ratos , Ventrículos do Coração/citologia , Miócitos Cardíacos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Troponina I/metabolismo , Imunoprecipitação , Miofibrilas , Miócitos Cardíacos/química , Fosforilação , Plasmídeos
16.
Eur J Clin Pharmacol ; 69(5): 1103-12, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23150151

RESUMO

PURPOSE: Chinese people are more frequent carriers of cytochrome P450 2C19 (CYP2C19) loss-of-function alleles than Caucasians. The effect of the ATP-binding cassette, sub-family B, member 1 (ABCB1), and paraoxonase 1 (PON1) variants on platelet reactivity and clinical outcomes of clopidogrel treatment has not yet been reported in Chinese patients after percutaneous coronary intervention. The aim of this study was to investigate the effect of the CYP2C19, ABCB1, and PON1 variants on clopidogrel pharmacodynamics and clinical outcomes in these patients. METHODS: Six hundred and seventy patients after percutaneous coronary intervention were enrolled in a single-center registry. The antiplatelet effect of clopidogrel was assessed by thromboelastography, and the CYP2C19, ABCB1, and PON1 genotypes were detected by the ligase detection reaction. Primary clinical endpoints included cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis. The secondary clinical endpoints were thrombolysis in myocardial infarction bleeding. The follow-up period was 12 months. RESULTS: The frequency of the CYP2C19 loss-of-function alleles was relatively high (57.3 %). The risk of a low response to clopidogrel and composite ischemic events increased with the number of CYP2C19 loss-of-function alleles. However, there were not significant differences in clopidogrel pharmacodynamics and clinical outcomes across the ABCB1 and PON1 genotype groups; bleeding was not significantly different across the CYP2C19, ABCB1, and PON1 genotype groups. CONCLUSIONS: The CYP2C19 loss-of-function alleles had a gene dose effect on the pharmacodynamics and composite ischemic events of clopidogrel in our study population. Neither the ABCB1 nor the PON1 genotype significantly influenced the antiplatelet effect and clinical outcomes of clopidogrel in these patients.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Hidrocarboneto de Aril Hidroxilases/genética , Arildialquilfosfatase/genética , Intervenção Coronária Percutânea , Sistema de Registros , Ticlopidina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Clopidogrel , Citocromo P-450 CYP2C19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único , Ticlopidina/efeitos adversos , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico
17.
Microvasc Res ; 84(1): 44-54, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22542438

RESUMO

OBJECTIVE: To investigate whether ischemic preconditioning (IP) can reduce myocardial no-reflow by activating endothelial (e-) nitric oxide synthase (NOS) via the protein kinase A (PKA) pathway. METHODS AND RESULTS: In a 90-min ischemia and 3-h reperfusion model, minipigs were assigned into sham, ischemia-reperfusion (IR), IR+IP, IR+IP+L-NNA (an eNOS inhibitor, 10mg·kg(-1)), IR+IP+H-89 (a PKA inhibitor, 1.0µg·kg(-1)·min(-1)), IR+L-NNA, and IR+H-89 groups. IP pretreatment improved cardiac function and coronary blood flow, decreased the activities of creatine kinase by 36.6% after 90 min of ischemia and by 32.8% after 3 h of reperfusion (P<0.05), reduced the no-reflow areas from 49.9% to 11.0% (P<0.01), and attenuated the infarct size from 78.2% to 35.4% (P<0.01). IP stimulated myocardial PKA activities and the expression of PKA and Ser(133) phosphorylated (p-) cAMP response element-binding protein (CREB) in the reflow and no-reflow myocardium, and enhanced the activities of constitutive NOS and the phosphorylation of eNOS at Ser(1179) and Ser(635) in the no-reflow myocardium. IP suppressed the expression of tumor necrosis factor-α and P-selectin, and attenuated cardiomyocytes apoptosis by regulating the expression of Bcl-2 and caspase-3 in the reflow and no-reflow myocardium. The eNOS inhibitor L-NNA completely canceled these beneficial effects of IP without any influence on PKA activity, whereas the PKA inhibitor H-89 partially blocked the IP cardioprotective effects and eNOS phosphorylation at the same time. CONCLUSION: IP attenuates myocardial no-reflow and infarction after ischemia and reperfusion by activating the phosphorylation of eNOS at Ser(1179) and Ser(635) in a partly PKA-dependent manner.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Precondicionamento Isquêmico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio Atordoado/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fenômeno de não Refluxo/patologia , Animais , Apoptose , Biomarcadores/metabolismo , Hemodinâmica , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio Atordoado/metabolismo , Miocárdio Atordoado/fisiopatologia , Miocárdio/enzimologia , Miocárdio/patologia , Fenômeno de não Refluxo/metabolismo , Fenômeno de não Refluxo/fisiopatologia , Fosforilação , Suínos , Porco Miniatura
18.
Zhonghua Xin Xue Guan Bing Za Zhi ; 40(11): 945-51, 2012 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-23363677

RESUMO

OBJECTIVE: Myocardial edema plays an important role in the development of myocardial no-reflow and reperfusion injury after the revascularization of acute myocardial infarction (AMI). The present study investigated whether the effect of ischemic preconditioning (IPC) against myocardial no-reflow and reperfusion injury was related to the reduction of myocardial edema through the protein kinase A (PKA) pathway. METHODS: Twenty-four minipigs were randomized into sham, AMI, IPC, and IPC + H-89 (PKA inhibitor, 1.0 µg · kg(-1) · min(-1)) groups. The area of no-reflow (ANR), area of necrosis (AN), and water content in left ventricle and ischemic-myocardium and non-ischemic area were determined by pathological studies. Microvascular permeability was determined by FITC-labeled dextran staining. Cardiomyocyte cross-sectional area (CSA) and mitochondria cross-sectional area (MSA) were evaluated by histological analysis. Myocardial expression of aquaporins (AQPs) was detected by Western blot. RESULTS: Compared with the MI group, the sizes of no-reflow and infarct were reduced by 31.9% and 46.6% in the IPC group (all P < 0.01), water content was decreased by 5.7% and 4.6% in the reflow and no-reflow myocardium of the IPC group (all P < 0.05), microvascular permeability and cardiomyocytes swelling in the reflow area were inhibited by 29.8% and 21.3% in the IPC group (all P < 0.01), mitochondrial water accumulation in the reflow and no-reflow areas of the IPC group were suppressed by 45.5% and 34.8% respectively (all P < 0.01), and the expression of aquaporin-4, -8, and -9 in the reflow and no-reflow myocardium were blocked in the IPC group. However, these beneficial effects of IPC were partially abolished in the IPC + H-89 group. CONCLUSIONS: The cardioprotective effects of IPC against no-reflow and reperfusion injury is partly related to the reduction of myocardial edema by inhibition of microvascular permeability and aquaporins up-regulation via PKA pathway.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Precondicionamento Isquêmico , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Aquaporinas/metabolismo , Permeabilidade Capilar , Edema/metabolismo , Edema/patologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Suínos , Porco Miniatura
19.
Zhonghua Xin Xue Guan Bing Za Zhi ; 39(7): 617-20, 2011 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-22088240

RESUMO

OBJECTIVE: To investigate the impact of cytochrome P450 (CYP) 2C19 681G > A polymorphism on long-term prognosis of clopidogrel-treated Chinese patients after percutaneous coronary intervention (PCI). METHODS: Between January 1, 2009 and August 31,2009, 267 patients with coronary heart disease who received PCI and treated with clopidogrel for 12 months were enrolled. CYP2C19 * 2 was detected by MALDI-TOF MS and patients were grouped into CYP2C19 * 1/ * 1 (n = 130) and CYP2C19 * 2 carriers group (n = 137). Follow-up was 12 months. The primary endpoint was angina recurrence, urgent coronary revascularization, acute myocardial infarction, stent thrombosis, death and the combined end points. RESULTS: Baseline data were similar between two groups (P > 0.05). Urgent coronary revascularization and the combined end points occurred more frequently in CYP2C19 * 2 carriers than in CYP2C19 * 1/* 1 patients (7.3% vs. 1.5% and 8.0% vs. 2.3% respectively, all P < 0.05). But incidence of angina recurrence, acute myocardial infarction, stent thrombosis and death was similar between two groups (all P > 0.05). Hazard risk of 1 year cumulative survival of CYP2C19 * 2 carriers group was significantly higher than CYP2C19 * 1/ * 1 group after PCI ( HR = 3.59, 95% CI: 1.02 - 12.87, P < 0.05). CONCLUSION: CYP2C19 681G > A polymorphism is a determinant of prognosis in coronary heart disease patients receiving chronic clopidogrel treatment after PCI.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Doença das Coronárias/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Angioplastia Coronária com Balão , Clopidogrel , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Citocromo P-450 CYP2C19 , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Ticlopidina/uso terapêutico
20.
Clin Exp Pharmacol Physiol ; 38(4): 278-84, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21314842

RESUMO

1. Cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific kinase gene. Quantitative real-time reverse transcription polymerase chain reaction analysis showed a significant increase in TNNI3K mRNA expression in hypertrophic cardiomyocytes induced by endothelin-1 (ET-1). The aim of the present study was to investigate the effects of TNNI3K on neonate rat cardiomyocyte hypertrophy induced by ET-1. 2. Adenoviruses were amplified in 293A cells. To determine a reasonable adenovirus infection dose cardiomyocytes were infected with an adenovirus carrying human TNNI3K (Ad-TNNI3K) at varying multiplicity of infection (MOI) and the expression of TNNI3K was analysed by western blot. 3. Cardiomyocytes were infected with either a control adenovirus carrying green fluorescent protein (Ad-GFP) or Ad-TNNI3K. Compared with Ad-GFP, the Ad-TNNI3K induced an increase in sarcomere organization, cell surface area, (3) H-leucine incorporation and ß-MHC re-expression. This type of hypertrophic phenomenon is similar to that observed in Ad-GFP-infected hypertrophic cardiomyocytes induced by ET-1. To determine the functional role of TNNI3K in ET-1-induced hypertrophic cardiomyocytes, the cells were infected with Ad-GFP or Ad-TNNI3K. Ad-TNNI3K induced an increase in sarcomere organization, cell surface area and (3) H-leucine incorporation compared with Ad-GFP. 4. These results suggest that TNNI3K overexpression induces cardiomyocytes hypertrophy and accelerates hypertrophy in hypertrophic cardiomyocytes. Therefore, TNNI3K might be an interesting target for the clinical treatment of hypertrophy.


Assuntos
Cardiomegalia/enzimologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Miócitos Cardíacos/enzimologia , Adenoviridae/genética , Animais , Células Cultivadas , Endotelina-1/farmacologia , Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Humanos , Leucina/metabolismo , MAP Quinase Quinase Quinases/biossíntese , Proteínas Serina-Treonina Quinases , Ratos , Ratos Sprague-Dawley , Sarcômeros/efeitos dos fármacos , Sarcômeros/enzimologia , Miosinas Ventriculares/biossíntese , Miosinas Ventriculares/genética
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